The Augusta founding laboratories have used cutting edge genetic technologies and shRNA screening methodologies to uncover the ROS receptor tyrosine kinase as a cancer survival gene. Studies from other laboratories have drawn a clear link between ROS kinase activity and the development and/or progression of astrocytic tumors such as glioblastoma, a grade IV astrocytoma, based on genetic findings, gene expression data, and animal models. Taken together, these findings validate a scientific rationale that links ROS kinase activity to glioblastoma metabolism and its associated patient morbidity and mortality. The overall objective of this proposal is to develop small molecules that inhibit the kinase activity of the ROS receptor tyrosine kinase for the primary indication of human glioblastoma multiforme (GBM). The specific objective of this proposal is to further develop prototype compounds using standard medicinal chemistry practices to generate more potent ROS inhibitors as judged by two approaches: 1) inhibition of enzymatic activity in vitro;and 2) selective growth inhibition of glioblastoma cells lines expressing aberrant ROS as compared to normal glial cells. If these criteria are satisfied, then we have validated a structurally optimized and biologically active molecule (i.e., a lead compound) that can be advanced to a Phase II program.